GPR: 2020 - Week 47

From MGH Learn Pathology

Clinical history

62 year old male, former beach lifeguard for 25 years, presents with new large growth on his back.


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TERT Promoter mutations
A 2017 Nature paper that conducted whole genome sequencing on 183 melanoma samples found 86% of cutaneous melanomas were mutated at 1 of 4 TERT promoter sites.
  • All 4 create new binding sites for ETS family TF GABP
  • Generally mutually exclusive
  • Only found in 11% of acral and mucosal melanomas



BRAF mutation

BRAF mutations are present in approximately 50% of cutaneous melanoma tumors
  • Most commonly V600E
  • V600K is next most common variant
  • K601 mutations are also recurrent



RAS family mutation

30-35% of melanomas contain mutations in RAS family member genes
  • NRAS mutations are most common at 28%. These occur at recurrent hotspots
  • HRAS and KRAS mutations are less frequent and may or may not be drivers
  • NRAS mutations, but not HRAS/KRAS, are generally mutually exclusive with BRAF mutations



NF1 gene mutation

NF1 gene mutations occur in 14-17% of melanoma cases
  • Mutations occur throughout gene body
  • Can be point, INDELs, structural variants
  • Activate MAPK pathway through loss of function (BRAF, RAS mutations are activating mutations that activate MAPK pathway).
  • Dr. Jochen Lennerz for conceptual inspiration
  • Dr. T. Leif Helland for gross image

This week's Gross Pathology Roundup was presented by Tyler Miller MD, PhD on 2020-11-16.